GLUCONEOGENESISGLUCONEOGENESIS

The process of forming sugar from non The process of forming sugar from non carbohydrate moleculescarbohydrate moleculesProtects the body (especially the brain) of Protects the body (especially the brain) of hypoglycemia hypoglycemia during prolonged fast , liver glycogen stores are during prolonged fast , liver glycogen stores are depleted depleted Substrates : Substrates : the glucogenic amino acids, lactate, the glucogenic amino acids, lactate, glycerol and propionateglycerol and propionateOccurs in Occurs in the cytosol and mitochondria the cytosol and mitochondria at the at the liver (90 %), kidney (10 %) liver (90 %), kidney (10 %)

GLUCONEOGENESISGLUCONEOGENESIS

Three irreversible reactions in glycolysis Three irreversible reactions in glycolysis circumvented by four alternate :circumvented by four alternate :

- Carboxylation of pyruvate to oxaloacetate by - Carboxylation of pyruvate to oxaloacetate by pyruvate carboxylasepyruvate carboxylase, converted to PEP by , converted to PEP by PEP PEP carboxykinasecarboxykinase

Oxaloacetate Oxaloacetate reduced to malate, reduced to malate, transported to transported to cytosol cytosol reoxidized to oxaloacetate reoxidized to oxaloacetate

- Dephosphorylation of fructose 1,6 bisphosphate - Dephosphorylation of fructose 1,6 bisphosphate by by fructose 1,6 bisphosphatasefructose 1,6 bisphosphatase

- Dephosphorylation of glucose 6 phosphate by - Dephosphorylation of glucose 6 phosphate by glucose 6 phosphataseglucose 6 phosphatase

REGULATION OF GLUCONEOGENESISREGULATION OF GLUCONEOGENESIS

By substrate availability, enzymes (By substrate availability, enzymes ( allosteric allosteric effectors) and hormoneseffectors) and hormonesSubstrate availability Substrate availability a high fat diet, starvation and a high fat diet, starvation and prolonged fastingprolonged fastingThe four key enzyme are affected by AMP, ATP, The four key enzyme are affected by AMP, ATP, Citrate, Acetyl co A, Fructose 2,6 BP, Citrate, Acetyl co A, Fructose 2,6 BP, Fructose 1,6 BPFructose 1,6 BPHormones : insulin, glucagon, cortisolHormones : insulin, glucagon, cortisol altering concentration of allosteric effectorsaltering concentration of allosteric effectors altering enzymes synthesisaltering enzymes synthesis

GLUCONEOGENESIS SUBSTRATESGLUCONEOGENESIS SUBSTRATES

Glucose synthesis from Glucose synthesis from lactatelactate- Lactate is released by cells have low oxygen - Lactate is released by cells have low oxygen concentrationsconcentrations- In the - In the cori cycle cori cycle ::lactate is released by skeletal muscle during lactate is released by skeletal muscle during exercise exercise transferred to the liver transferred to the liver pyruvate pyruvate glucose glucose gluconeogenesis gluconeogenesis

LACTIC ACID (CORI) CYCLELACTIC ACID (CORI) CYCLE  glucose glucose glucose glucose-6-P glucose-6-P glycogen glycogen  ATP ATP  NADH Blood NADH pyruvate pyruvate  lactate lactate lactate Liver Muscle

GLUCONEOGENESIS SUBSTRATESGLUCONEOGENESIS SUBSTRATES

Glucose synthesis from Glucose synthesis from GlycerolGlycerol

- Glycerol, a product of fat metabolism in - Glycerol, a product of fat metabolism in adipose tissue adipose tissue transported to the transported to the liverliverconverted to glycerol 3 phosphate by converted to glycerol 3 phosphate by glycerol kinase glycerol kinase ((only in liver and kidneyonly in liver and kidney))

Liver and kidney are able to convert glycerol Liver and kidney are able to convert glycerol glucoseglucose

GLUCONEOGENESIS SUBSTRATESGLUCONEOGENESIS SUBSTRATES

Glucose synthesis from the Glucose synthesis from the glucogenic amino glucogenic amino acidsacids

- - Alanin Alanin the most important as the most important as glucogenic amino glucogenic amino acidsacids

- When exercising muscle produces large - When exercising muscle produces large quantities of pyruvatequantities of pyruvate alanine alanine transported to transported to the liver the liver reconverted to pyruvate and then to reconverted to pyruvate and then to glucoseglucose

Alanine CycleAlanine Cycle

Frc-2,6-bisP effects in liverFrc-2,6-bisP effects in liver

Frc-2,6 bisP : allosteric effector of PFK 1 and Frc-2,6 bisP : allosteric effector of PFK 1 and fructose 1,6 bisphosphatase in liverfructose 1,6 bisphosphatase in liver

Formed by phosphorylation of fructose 6 phosphate Formed by phosphorylation of fructose 6 phosphate by PFK 2by PFK 2

When blood [Glc] is low, When blood [Glc] is low, glucagonglucagon is released, is released, resulting in increased intracellular [cAMP] in liver. resulting in increased intracellular [cAMP] in liver. – Frc-2,6-bisP decreases, stimulates Frc-2,6-bisP decreases, stimulates

gluconeogenesisgluconeogenesis

When blood [Glc] is high, Frc-2,6-bisP increasesWhen blood [Glc] is high, Frc-2,6-bisP increases– Inhibiting Fructose 1,6 bisphosphatase, inhibiting Inhibiting Fructose 1,6 bisphosphatase, inhibiting

gluconeogenesisgluconeogenesis

CLINICAL ASPECTSCLINICAL ASPECTS

GlycosuriaGlycosuriaNormal, the concentration of blood glucose in Normal, the concentration of blood glucose in individual humans is within the range 4,5 - 5,5 individual humans is within the range 4,5 - 5,5 mmol/L mmol/L

When the blood glucose rise to relatively high When the blood glucose rise to relatively high level, the kidney exerts a regulatory effectlevel, the kidney exerts a regulatory effect

The glomerular filtrate may contain more The glomerular filtrate may contain more glucose than can be reabsorbed glucose than can be reabsorbed

CLINICAL ASPECTSCLINICAL ASPECTS

GlycosuriaGlycosuria

The excess passes into the urine to produce The excess passes into the urine to produce GlycosuriaGlycosuria

Normal individual : glycosuria occurs when the Normal individual : glycosuria occurs when the venous blood glucose concentration : venous blood glucose concentration :

> 9,5 – 10 mmol/l > 9,5 – 10 mmol/l

This is termed Renal Treshold for glucose This is termed Renal Treshold for glucose